Lymphocyte homing from the circulation to the lymphoid tissues and migration to sites of inflammation is regulated by interaction with receptors expressed in postcapillary venules, including high endothelial venules (HEV) found in secondary lymphoid tissues (e.g., mesenteric lymph nodes, Peyer's Patches (PP)) (Bevilacqua, M. P., Annu. Rev. Immunol., 11: 767-804 (1993); Butcher, E. C., Cell, 67: 1033-1036 (1991); Picker, L. J., et al., Annu. Rev. Immunol., 10: 561-591 (1992); and Springer, T. A., Cell, 76: 301-314 (1994)). These interactions are tissue specific in nature.
Inflammation (e.g., chronic inflammation) is characterized by infiltration of the affected tissue by leukocytes, such as lymphocytes, lymphoblasts, and mononuclear phagocytes. The remarkable selectivity by which leukocytes preferentially migrate to various tissues during both normal circulation and inflammation results from a series of adhesive and activating events involving multiple receptor-ligand interactions as proposed by Butcher and others (Butcher, E. C., Cell, 67: 1033-1036 (1991); vonAdrian, U. H., et al., Proc. Natl. Acad. Sci. USA, 88: 7538 (1991); Mayadas, T. N., et al., Cell, 74: 541 (1993); Springer, T. A., Cell, 76: 301 (1994)). As an initial step, there is a transient, rolling interaction between leukocytes and endothelium, which results from the interaction of selectins (and by α4 integrins in some instances) with their carbohydrate ligands. This interaction which is characterized by rolling in the direction of flow can be assessed by known methods (Lawrence, M. B. and T. A. Springer, Cell, 65: 859 (1991); WO 92/21746, Springer et al., (Dec. 10, 1992)). This is followed by activation events mediated by chemoattractants such as chemokines and their receptors, which cause activation of integrin adhesiveness and influence the direction of migration of leukocytes through vascular walls. Such secondary signals in turn trigger the firm adhesion of leukocytes to endothelium via leukocyte integrins and their endothelial ligands (Ig-like receptors and the ECM), and subsequent transendothelial migration from the circulation across the vascular endothelium.
In secondary lymphoid tissues, such as Peyer's patches (PPs) and lymph nodes (e.g., peripheral lymph nodes (PLN)), leukocyte trafficking and homing is regulated by interactions of homing receptors on the surface of leukocytes with endothelial cells lining the post-capillary venules, notably high endothelial venules (HEV) (Gowans, J. L. and E. J. Knight, Proc. R. Soc. Lond., 159: 257 (1964)). Receptors termed vascular addressins, which are present on the endothelial cell surface and regulate the migration and subsequent extravasation of lymphocyte subsets. The vascular addressins show restricted patterns of expression and this tissue specific expression makes an important contribution to the specificity of leukocyte trafficking (Picker, L. J. and E. C. Butcher, Annu. Rev. Immunol., 10: 561-591 (1992); Berg, E. L., et al., Cellular and molecular mechanisms of inflammation, 2: 111 (1991); Butcher, E. C., Cell, 67: 1033-1036 (1991)).
Mucosal vascular addressin MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule-1) is an immunoglobulin superfamily adhesion receptor for lymphocytes, which is distinct from VCAM-1 and ICAM-1. MAdCAM-1 was identified in the mouse as a ˜60 kd glycoprotein which is selectively expressed at sites of lymphocyte extravasation. In particular, MAdCAM-1 expression was reported in vascular endothelial cells of mucosal tissues, including gut-associated tissues or lymphoid organs, such as Peyer's patches and venules of the lamina propria of the small and large intestine, and the lactating mammary gland, but not in peripheral lymph nodes. MAdCAM-1 is involved in lymphocyte binding to Peyer's Patches. (Streeter, P. R., et al., Nature, 331:41-46 (1988); Nakache, M., et al., Nature, 337: 179-181 (1989); Picker, L. J., et al., Annu. Rev. Immunol., 10: 561-591 (1992); Briskin, M. J., et al., Nature, 363: 461 (1993); Berg, E. L., et al., Nature, 366: 695-698 (1993); Berlin, C., et al., Cell, 74: 185-195 (1993)). MAdCAM-1 can be induced in vitro by proinflammatory stimuli (Sikorski, E. E., et al., J. Immunol., 151: 5239-5250 (1993)).
MAdCAM-1 specifically binds the lymphocyte integrin α4β7 (also referred to as LPAM-1 (mouse), α4βp (mouse)), which is a lymphocyte homing receptor involved in homing to Peyer's patches (Berlin, C., et al., Cell, 80: 413-422 (1994); Berlin, C., et al., Cell, 74: 185-195 (1993); and Erle, D. J., et al., J. Immunol., 153: 517-528 (1994)). In contrast to VCAM-1 and fibronectin, which interact with both α4β1 and α4β7 (Berlin, C., et al., Cell, 74: 185-195 (1993); Strauch, U. S., et al., Int. Immunol., 6: 263 (1994)), MAdCAM-1 is a selective receptor for α4β7.
Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, for example, can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract. Affecting an estimated two million people in the United States alone, symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as, corticosteroids and sulfasalazine), immunosuppressive drugs (such as, 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky, New Engl. J. Med., 325: 928-937 (1991) and Podolsky, New Engl. J. Med., 325: 1008-1016 (1991).
Some studies have suggested that the cell adhesion molecule, ICAM-1, mediates leukocyte recruitment to inflammatory sites through adhesion to leukocyte surface ligands, i.e., Mac-1 or LFA-1 (Springer, Nature, 346: 425-434 (1990)). In addition, vascular cell adhesion molecule-1 (VCAM-1), which recognizes the α4β1 integrin (VLA-4), has been reported to play a role in in vivo leukocyte recruitment (Silber et al., J. Clin. Invest. 93: 1554-1563 (1994)). It has been proposed that IBD can be treated by blocking the interaction of ICAM-1 with LFA-1 or Mac-1, or of VCAM-1 with α4β1 (e.g., WO 93/15764). However, these therapeutic targets are likely to be involved in inflammatory processes in multiple organs, and a functional blockade could cause systemic immune dysfunction.
In contrast to VCAM-1 and ICAM-1, MAdCAM is preferentially expressed in the gastrointestinal tract, binds the α4β7 integrin found on lymphocytes, and participates in the homing of these cells to mucosal sites, such as Peyer's patches in the intestinal wall (Hamann et al., Journal of Immunology, 152: 3282-3293 (1994)). The use of inhibitors to the binding of MAdCAM to the receptor, α4β7, in the treatment of diseases such as IBD has not been suggested. Moreover, although human α4 and β7 genes and proteins have been identified (Yuan et al., Int. Immunol., 2: 1097-1108 (1990); Erle et al., J. Biol. Chem., 266: 11009-11016 (1991); Bevilacqua, M. P., Annu. Rev. Immunol., 11: 767-804 (1993); Springer, T. A., Cell, 76: 301-314 (1994)), human or primate MAdCAM-1 has not been cloned or characterized.